Tetrahedron Letters 53 (2012) 4354–4356
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Iron triflate catalyzed reductive amination of aldehydes using sodium borohydride N. Uday Kumar a, B. Sudhakar Reddy a, V. Prabhakar Reddy b, Rakeshwar Bandichhor a,⇑ a b
Integrated Product Development, Innovation Plaza, Dr. Reddy’s Laboratories Ltd, Bachupalli, Qutubullapur, R.R. Dist. 500072, Andhra Pradesh, India Department of Chemistry, Osmania University, Hyderabad 500007, India
a r t i c l e
i n f o
Article history: Received 13 April 2012 Revised 1 June 2012 Accepted 6 June 2012 Available online 12 June 2012
a b s t r a c t An efficient and convenient procedure for the reductive amination of aldehydes using NaBH4 in the presence of catalytic amount of Fe(OTf)3 is described. Ó 2012 Elsevier Ltd. All rights reserved.
Keywords: Reductive amination Iron triflate Sodium borohydride
Direct reductive amination of aldehydes in one pot is an important transformation in organic synthesis from process efficiency standpoint. Wherein, alternatively, indirect or two step reductive amination involves isolation of imine derivative with impeded efficiency (Scheme 1). There are two types of reducing agents employed for direct reductive amination of aldehydes with amines. These two strategies are mainly based on metal catalyzed hydrogenation and hydride reducing agents. The metal catalyzed hydrogenation has limitations to many substrates which has reducible functionalities apart from imines.1 There is another excellent Borch reduction approach, one of the early methods that involves sodium cyanoborohydride.2a In addition to this, derivatives of cyano borohydride in combination with other reagents2b–f are also being used but the cyanoborohydride derivatives suffer from the formation of highly toxic byproducts such as HCN and NaCN. Numerous alternative reagents such as NaBH(OAc)3,3a TiCl(OiPr)3/NaBH(OAc)3,3b NiCl2/ NaBH4,4a NaBH4/ZnCl2,4b NaBH4/ZrCl4,4c Ti(OiPr)4/NaBH4,4c NaBH4/ H2SO4,4d NaBH4/wet clay,4e solid acid activated NaBH4,4f NaBH4/ H3PW12O40,4g NaBH4/Bronsted acidic ionic liquid,4h NaBH4/(GuHCl),4i borohydride exchange resin,5 pyridine/borane,6 picoline/borane,7 diborane/MeOH,8 decaborane,9 ZnBH4,10a ZnBH4/ZnCl2,10b ZnBH4/SiO2,10c Zn/AcOH,11 PMHS/Ti(OiPr)4,12a PMHS/ZnCl2,12b PMHS/BuSn(OCOR)3,12c Et3SiH/CF3CO2H,12d PhMe2SiH/(C6F6)3,12e Cl3SiH/DMF,12f PhSiH3/Bu2SnCl2,12g PMHS/TFA,12h nBu3SnH/DMF or HMPA,13a nBu3SnH/SiO213b and nBu2SnIH or nBu2/SnClH,13c,d Zr(BH4)4/piperazine,14 hydrio-iridium(III) complex,15 iridium ⇑ Corresponding author. E-mail address:
[email protected] (R. Bandichhor). 0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2012.06.018
complex,16 FeII/EDTA complex,17 LiBH4,18 ammoniaborane/ Ti(OiPr)4,19 bis(triphenylphosphine)copper(I) tetrahydroborate,20 molybdenum dioxide dichloride and phenylsilane21 etc. have been reported.4f Moreover, reagents containing zinc and Ti(OiPr)4 mediated are not suitable for chemoselective reductions.22 Usage of tin hydrides is not suitable due to toxicity in large scale production as the removal of residual tin is found to be extremely difficult. Recently, Hantzsch method that involves dihydropyridine as reductant (removal of toxic pyridine is found to be extremely difficult) in the presence of scandium triflate as a catalyst,23 S-benzyl isothiouronium chloride as a recoverable organocatalyst along with dihydropyridine,24 Pd(PhCN)2Cl2/2,20 -biquinoline-4,40 -dicarboxylic acid dipotassium salt (BQC)25 and Leuckart type reductive amination26 are also reported for reductive amination. Metal triflate catalyzed reductive amination procedures are well documented. In most of the cases, the metals as part of catalysts are not suitable for the synthesis of active pharmaceutical ingredients (APIs) due to regulatory requirements as one has to limit the traces of them in the order of ppms (parts per millions).27 Direct H O R catalyst
catalyst
NHR 1
reagent R reagent
H 1
NR R Indirect
Scheme 1. Direct and indirect reductive amination.
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N. Uday Kumar et al. / Tetrahedron Letters 53 (2012) 4354–4356
Class 1 (toxic) Pt, Pd, Ir, Rh, Ru, Os Mo, Ni, Cr, V
Class 2 (less toxic)
Class 3 (non-toxic)
Cu, Mn, Ti, Sc
O
O
Zn, Fe
R
H
Fe(OTf) 3
Figure 1. Comparative toxicological classification of the metals.
NR1
1 mol% Fe(OTf) 3
O H 2NR 1
1 eq. NaBH4
OLA
R R1 N
N H
N H
3b 90%
N H 3c 92% NHPh
NHPh N H
Ph CF3 3f 88%
Cl 3d 90%
3e 80% NHPh
NHPh O
F
NHPh EtO 3i 82%
3h 90%
3g 90% NHPh H 3CO OCH3
N H C 2 H5 O
3j 87% N H C 2H 5O
Cl
3k 88%
Ph
N H NO 2
3l 89% N H
N H
Ph O2 N
N H
Ph
Ph
3o 90%
O 2N
N H OH
H 3 CO OCH 3 3p 90% N H
Ph
3m 92%
3n 89%
Ph
3q 90% H N
Ph
CF 3
CF 3 3r 89%
3s Cinacalcet 80% O O
O
R1
H N
NaBH4
H H
R R1
NH
H 2O
Scheme 3. Possible mechanism for direct amination.
Ph 3a 90%
NH2 R1 H (TfO) 3 Fe O R H
H H
Ph
R R1 N
H
H
H
R 2 3 (a-t) R, R 1 = alkyl,aryl or heterocyclic
R 1
R
OLA
LA
O HN O Ph 3t Aliskiren intermediate 88%
Scheme 2. Fe(OTf)3 catalyzed reductive amination of carbonyl compounds.
In order to do so, a tedious workup is required that becomes costly affair due to material loss. Therefore, we attempted to develop non- or less toxic metal triflate which is readily and cheaply available in the market. In comparison to other metals (Fig. 1),27 Fe is
most widely recommended due to its non-toxic nature. Such a strategy that features Fe(OTf)3/NaBH4 reducing system provides very efficient and workable protocol to address the associated industrial problems up to great extent from three standpoints; (1) reduced duration of the reaction, (2) high conversion and (3) relaxed specification for metal content as Fe in pharmaceutical products is relatively much safer as per the US FDA guidelines.27 This adds to a better process efficiency as one can avoid purifications and thereby increase the isolated yield in comparison to hitherto known procedures. In our endeavor, catalytic quantity of iron triflate (Fe(OTf)3 along with NaBH4 was opted for direct reductive amination. Sodium borohydride is an inexpensive reducing agent which stands alone known to reduce imines and other functionalities limiting its application in broader sense. Moreover, it is understood that the poor electrophilic carbonyls, poor nucleophilic amines, and sterically crowded reactive centers do not favor the completion of imine formation. Thus, it is quite apparent that NaBH4 alone may not afford excellent yields. Strategically, we employed the combination of 1 mol % Fe(OTf)3 along with stoichiometric amount of NaBH4 for the first time in the direct reductive amination. This strategy was demonstrated with various aldehydes and amines. The reaction of aldehydes 1 with amines 2 proceeded smoothly in CH2Cl2 with excellent yields as shown in Scheme 2.30 In most of the cases, we obtained pure products hence there was no need to involve column chromatography. The catalytic activity of Fe(OTf)3 in reductive amination, was probed by conducting the control experiment without the catalyst. In this control experiment, we found that only NaBH4 did not afford clean imine rather we encountered incomplete reaction as well as alcohol as a byproduct. This strategy was extended not only to model substrates but it has found application in the synthesis of pharmaceutically relevant intermediates for example, Cinacalcet (3s)28 and Aliskiren (3t).29 Mechanistically, iron triflate as a Lewis acid activates the carbonyl functionality and provides very reactive electrophile source. Amine that was used as substrate reacts with the activated aldehyde to afford hemiaminol equivalent. Thereafter, dehydration event regenerates the catalyst. In situ generated imine can further be reduced with sodium borohydride affording the products as shown in Scheme 3. Our approach allowed us to have quick access of the products as the rate of the reaction was found to be very fast (in the order of minutes) in comparison with the non-catalytic reactions for example, NaBH(OAc)3,3a mediated reactions take 2 h–10 d for such type of reductive amination. We have developed and demonstrated novel method by involving catalytic quantity of iron triflate and sodium borohyderide (1 equiv) which can be considered as synthetically useful reagent system for reductive amination in one pot.
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Acknowledgements We are grateful to the management of Dr. Reddy’s Laboratories Ltd for supporting this work. We are thankful to NMR group of DRF for their assistance. Dr. Reddy’s communication number IPDO IPM-00327. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2012. 06.018. References and notes 1. (a) Rylabder, P. N. Hydrogenation Methods; Academic: NewYork, 1985; (b) Tarasevich, V. A.; Kozlov, N. G. Russ. Chem. Rev. 1999, 68, 55. 2. (a) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897; (b) Borch, R. F.; Durst, H. D. J. Am. Chem. Soc. 1969, 91, 3996; (c) Hutchins, R. O.; Markowitz, M. J. Org. Chem. 1981, 46, 3571; (d) Kim, S.; Oh, C. H.; Ko, J. S.; Ahn, K. H.; Kim, Y. J. J. Org. Chem. 1927, 1985, 50; (e) Mattson, R. J.; Pham, K. M.; Leuck, D. J.; Cowen, K. A. J. Org. Chem. 1990, 55, 2552; (f) Brussee, J.; van Benthem, R. A. T. M.; Kruse, C. G.; Van der Gen, A. Tetrahedron: Asymmetry 1990, 1, 163. 3. (a) Abdel-Magid, A. F.; Carson, K. G.; Haris, B. D.; Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849; (b) Gutierrez, C. D.; Bavetsias, V.; McDonald, E. Tetrahedron Lett. 2005, 46, 3595. 4. (a) Periasamy, M.; Devasagayaraj, A.; Satyanarayana, N.; Narayana, C. Synth. Commun. 1989, 19, 565; (b) Itsuno, S.; Sakurai, Y.; Ito, K. Chem. Commun. 1988, 995; (c) Bhattacharyya, S. J. Org. Chem. 1995, 60, 4928; (d) Verardo, G.; Giumanini, A. G.; Strazzolini, P.; Poiana, M. Synthesis 1993, 121; (e) Varma, R. S.; Dahiya, R. Tetrahedron 1998, 54, 6293; (f) Cho, B. T.; Kang, S. K. Tetrahedron 2005, 61, 5725; (g) Heydari, A.; Khaksar, S.; Akbari, J.; Esfandyari, M.; Pourayoubi, M.; Tajbakhsh, M. Tetrahedron Lett. 2007, 48, 1135; (h) Reddy, S. P.; Kanjilal, S.; Sunitha, S.; Prasad, B. N. R. Tetrahedron Lett. 2007, 48, 8807; (i) Akbar, H.; Afsaneh, A.; Maryam, E. J. Mol. Catal. A-Chem. 2007, 274, 169. 5. Yoon, N. M.; Kim, E. G.; Son, H. S.; Choi, J. Synth. Commun. 1993, 23, 1595. 6. (a) Bomann, M. D.; Guch, I. C.; DiMare, M. J. Org. Chem. 1995, 60, 5995; (b) Pelter, A.; Rosser, R. M.; Mills, S. J. Chem. Soc., Perkin Trans. 1 1984, 717. 7. Sato, S.; Sakamoto, T.; Miyazawa, E.; Kikugawa, Y. Tetrahedron 2004, 60, 7899. 8. Nose, A.; Kudo, T. Chem. Pharm. Bull. 1986, 34, 4817. 9. Bae, J. W.; Lee, S. H.; Cho, Y. J.; Yoon, C. M. J. Chem. Soc., Perkin Trans. 1 2000, 145. 10. (a) Kotsuki, H.; Yoshimura, N.; Kadota, I.; Ushio, Y.; Ochi, M. Synthesis 1990, 401; (b) Bhattacharyya, S.; Chatterjee, A.; Williamson, J. S. Synth. Commun. 1997, 27, 4265; (c) Ranu, B. C.; Majee, A.; Sarkar, A. J. Org. Chem. 1998, 63, 370. 11. Micc´ovic´, I. V.; Ivanovic´, M. D.; Piatak, D. M.; Bojic´, V. D. Synthesis 1991, 1043.
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